Replacement with sex steroids in hypopituitary men and women: implications for gender differences in morbidities and mortality

Abstract

Hypopituitarism is a heterogenous disorder characterised by a deficiency in one or more anterior pituitary hormones. There are marked sex disparities in the morbidity and mortality experienced by patients with hypopituitarism. In women with hypopituitarism, the prevalence of many cardiovascular risk factors, myocardial infarction, stroke and mortality are significantly elevated compared to the general population, however in men, they approach that of the general population. The hypothalamic-pituitary-gonadal axis (HPG) is the most sexually dimorphic pituitary hormone axis. Gonadotropin deficiency is caused by a deficiency of either hypothalamic gonadotropin-releasing hormone (GnRH) or pituitary gonadotropins, namely follicle-stimulating hormone (FSH) and luteinising hormone (LH). HPG axis dysfunction results in oestrogen and testosterone deficiency in women and men, respectively. Replacement of deficient sex hormones is the mainstay of treatment in individuals not seeking fertility. Oestrogen and testosterone replacement in women and men, respectively, have numerous beneficial health impacts. These benefits include improved body composition, enhanced insulin sensitivity, improved atherogenic lipid profiles and increased bone mineral density. Oestrogen replacement in women also reduces the risk of developing type 2 diabetes mellitus. When women and men are considered together, untreated gonadotropin deficiency is independently associated with an increased mortality risk. However, treatment with sex hormone replacement reduces the mortality risk comparable to those with an intact gonadal axis. The reasons for the sex disparities in mortality remain poorly understood. Potential explanations include the reversal of women's natural survival advantage over men, premature loss of oestrogen's cardioprotective effect, less aggressive cardiovascular risk factor modification and inadequate oestrogen replacement in women with gonadotropin deficiency. Regrettably, historical inertia and unfounded concerns about the safety of oestrogen replacement in women of reproductive age have impeded the treatment of gonadotropin deficiency.

Keywords: Gonadotropin deficiency; Hypogonadotropic hypogonadism; Hypopituitarism; Mortality; Oestrogen; Sex hormone; Testosterone.

Fig. 1

Prevalence of comorbidities in hypopituitarism versus the general population by sex

Fig. 2

Impact of sex hormone replacement in women and men

Fig. 3

Comparison of SMRs in individuals with untreated gonadotropin deficiency, treated gonadotropin deficiency and an intact gonadal axis. The SMR was significantly higher in those with untreated gonadotropin deficiency compared to those who received sex hormone replacement (SMR 2.97 [99% CI, 2.13–4.13] v’s 1.42 [99% CI, 0.97–2.07], p < 0.0001). These results were not analysed by sex. (with permission) [5]

Fig. 4

Association between SMR and year of first hypopituitarism diagnosis in individual studies. There was a significant negative correlation between the SMR and year of first diagnosis. When analysed separately by sex, the correlation was significant in men but not women (with permission) [117]